Functional impairment of antigen-specific T cells is a defining characteristic of chronic infections in humans but the molecular mechanisms underlying this T-cell dysfunction are not well understood1. In contrast to the T cell response in acute infections, CD8+ T cells in chronic infection develop a range of functional defects that include the loss of IL2 secretion and proliferative potential2,3. Because cytokine secretion and proliferation are essential for effective control of viral replication, these defects—collectively referred to as T cell exhaustion—play a central role in the immunological failure to clear chronic viral pathogens such as HIV, HCV and HBV1.
HIV infection provides a paradigm of T cell dysfunction in humans. The majority of individuals infected with HIV show elevation of viral load in the absence of anti-viral therapy (hereafter, “chronic progressors”) associated with defects in HIV-specific T cell cytokine secretion, proliferation and survival12,13. In contrast, spontaneous control of viral replication has been documented for a small minority of individuals (‘controllers’)11.
BATF is a highly conserved member of the AP-1/ATF family, a group of transcription factors that regulate many aspects of cellular function in the immune system, including cytokine secretion and proliferation30. BATF antagonizes AP-1 function by dimerizing to Jun, disrupting the active Jun:Fos complex of AP-1, and reducing expression of AP-1 target genes20,24,31. Consistent with this, enforced expression of BATF in T cells inhibited the secretion of IL2, an AP-1 dependent gene, but not IFNγ which is not primarily regulated by AP-1.
Schraml et al. have found BATF to be required for Th17 differentiation in CD4+ T cells33.